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doi:10.22028/D291-35245
Titel: | Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages |
VerfasserIn: | Hoppstädter, Jessica Dembek, Anna Höring, Marcus Schymik, Hanna S. Dahlem, Charlotte Sultan, Afnan Wirth, Natalie Al-Fityan, Salma Diesel, Britta Gasparoni, Gilles Walter, Jörn Helms, Volkhard Huwer, Hanno Simon, Martin Liebisch, Gerhard Schulz, Marcel H. Kiemer, Alexandra K. |
Sprache: | Englisch |
Titel: | EBioMedicine |
Bandnummer: | 72 |
Seiten: | 2352-3964 |
Verlag/Plattform: | Elsevier |
Erscheinungsjahr: | 2021 |
Freie Schlagwörter: | Non-small cell lung cancer innate immune response ABCA1 ABCG1 ATR-101 |
DDC-Sachgruppe: | 500 Naturwissenschaften |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | Background Based on reports on elevated cholesterol levels in cancer cells, strategies to lower cholesterol synthesis have been suggested as an antitumour strategy. However, cholesterol depletion has also been shown to induce tumour-promoting actions in tumour-associated macrophages (TAMs). Methods We performed lipidomic and transcriptomic analyses of human lung cancer material. To assess whether the TAM phenotype is shaped by secreted factors produced by tumour cells, primary human monocyte-derived macrophages were polarized towards a TAM-like phenotype using tumour cell-conditioned medium. Findings Lipidomic analysis of lung adenocarcinoma (n=29) and adjacent non-tumour tissues (n=22) revealed a significant accumulation of free cholesterol and cholesteryl esters within the tumour tissue. In contrast, cholesterol levels were reduced in TAMs isolated from lung adenocarcinoma tissues when compared with alveolar macrophages (AMs) obtained from adjacent non-tumour tissues. Bulk-RNA-Seq revealed that genes involved in cholesterol biosynthesis and metabolism were downregulated in TAMs, while cholesterol efflux transporters were upregulated. In vitro polarized TAM-like macrophages showed an attenuated lipogenic gene expression signature and exhibited lower cholesterol levels compared with non-polarized macrophages. A genome-wide comparison by bulk RNA-Seq confirmed a high similarity of ex vivo TAMs and in vitro TAM-like macrophages. Modulation of intracellular cholesterol levels by either starving, cholesterol depletion, or efflux transporter inhibition indicated that cholesterol distinctly shapes macrophage gene expression. Interpretation Our data show an opposite dysregulation of cholesterol homeostasis in tumour tissue vs. TAMs. Polarization of in vitro differentiated macrophages by tumour cell-conditioned medium recapitulates key features of ex vivo TAMs. |
DOI der Erstveröffentlichung: | 10.1016/j.ebiom.2021.103578 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-352456 hdl:20.500.11880/32173 http://dx.doi.org/10.22028/D291-35245 |
ISSN: | 2352-3964 |
Datum des Eintrags: | 12-Jan-2022 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary materials |
In Beziehung stehendes Objekt: | https://ars.els-cdn.com/content/image/1-s2.0-S2352396421003716-mmc1.pdf |
Fakultät: | NT - Naturwissenschaftlich- Technische Fakultät |
Fachrichtung: | NT - Biowissenschaften NT - Pharmazie |
Professur: | NT - Prof. Dr. Volkhard Helms NT - Prof. Dr. Alexandra K. Kiemer NT - Prof. Dr. Jörn Walter |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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1-s2.0-S2352396421003716-main.pdf | 5,03 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons